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US 2003/0225149 A1Published application
Process for preparing highly functionalized gamma-butyrolactams and gamma-amino acids
OwnerPeter G. Blazecka, James Guy Davidson III +1inventors
InventorsPeter G. Blazecka, James Guy Davidson III, Ji Zhang
Life of this patent
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Abstract
The invention relates to a process for preparing highly functionalized γ-butyrolactams and γ-amino acids by reductive amination of mucohalic acid or its derivatives, and discloses a process for preparing pregabalin, a GABA analog with desirable medicinal activity. 1
Claims30
A process for preparing a compound of formula I
- 77
- wherein:
- R1 is H, (C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, (CH2)n-aryl, heterocyclo, (CH2)n-heterocyclo, heteroaryl, or (CH2)n-heteroaryl, wherein n is 0, 1, 2, or 3;
- and
- R2 and R2′ are each independently H, straight or branched (C1-C6)alkyl, a straight or branched (C2-C7)alkenyl, (C3-C7)cycloalkyl, alkylcycloalkyl, alkylalkoxy, alkylphenyl, alkyphenoxy, phenyl or substituted phenyl;
- comprising:
- (a) treating mucochloric or mucobromic acid 1 wherein X is Cl or Br with R′OH, wherein R′ is (C1-C6)alkyl, —CH2-phenyl, or —CH2-substituted phenyl in the presence of acid to provide 2A
- 78
- (b) conjugate addition of R2R2′CM0 wherein R2 and R2′ are as defined above and wherein M0 is MgBr, CuBr, or B(OH)2, to 2A, to provide 3A
- 79
- (c) hydrogenation of 3A to provide 4A
- 80
- (d) reductive amination of 4A under hydrogenation conditions using ammonium formate or R1NH2, wherein R1 is H, (C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, (CH2)n-aryl, heterocyclo, (CH2)n-heterocyclo, heteroaryl, or (CH2)n-heteroaryl, wherein n is 0, 1, 2, or 3, followed by hydrolyisis
- 81
11 more elements
A process for preparing pregabalin
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- comprising:
- (a) treating mucochloric or mucobromic acid 1 wherein X is Cl or Br with benzyl amine in the presence of acid, to provide 2
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- (b) conjugate addition of
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- wherein M1 is MgBr, CuBr, or
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- wherein M2 is B(OH)2, to 2 to provide 3B, wherein “———” is absent or is a bond;
- 87
- (c) hydrogenation of 3B to provide 4B
- 88
- (d) reductive amination of 4B using ammonium formate, followed by hydrolyisis
- 89
11 more elements
A process for preparing a compound of formula I
- 90
- wherein:
- R1 is H, (C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, (CH2)n-aryl, heterocyclo, (CH2)n-heterocyclo, heteroaryl, or (CH2)n-heteroaryl, wherein n is 0, 1, 2, or 3;
- and
- R2 and R2′ are each independently H, straight or branched (C1-C6)alkyl, a straight or branched (C2-C7)alkenyl, (C3-C7)cycloalkyl, alkylcycloalkyl, alkylalkoxy, alkylphenyl, alkyphenoxy, phenyl or substituted phenyl;
- comprising:
- (a) reductive amination of mucochloric or mucobromic acid 1 wherein X is Cl or Br, using a reducing agent in the presence of ammonium formate or R1NH2, wherein R1 is (C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, (CH2)n-aryl, heterocyclo, (CH2)n-heterocyclo, heteroaryl, or (CH2)n-heteroaryl, wherein n is 0, 1, 2, or 3, and an acid catralyst, to provide 2C
- 91
- (b) conjugate addition of R2R2′M0 wherein M0 is MgBr, CuBr, or B(OH)2, to 2C to provide 3C
- 92
- (c) hydrogenation of 3C to provide 4C
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- (d) hydrolysis of 4C
- 94
11 more elements
A process for preparing pregabalin
- 95
- comprising:
- (a) reductive amination of mucochloric or mucobromic acid 1 wherein X is Cl or Br using sodium triacetoxy borohydride in the presence of benzylamine or 1-phenyl-ethylamine to provide 2D
- 96
- (b) conjugate addition of
- 97
- to provide 3B, wherein “———” is absent or is a bond;
- 98
- (c) hydrogenation of 3D to provide 4D
- 99
- (d) base hydrolysis of 4D
- 100
9 more elements
A process for reductively aminating mucohalic acid, comprising:
- (a) contacting mucochloric or mucobromic acid 1 wherein X is Cl or Br with sodium triacetoxyborohydride, acetic acid, and R3NH2, wherein R3 is H, (C1-C8)alkyl, (C3-C7)cycloalkyl, aryl, (CH2)n-aryl, heterocyclo, (CH2)n-heterocyclo, heteroaryl, or (CH2)n-heteroaryl, wherein n is 0, 1, 2, or 3;
- to provide 2E
- 101
Dependencies are inferred from the claim text.